Peptidic or non-peptidic bioactive substances are known to exhibit various pharmacological activities in a living body, and the application thereof as medicaments have been attempted. However, it is required to administer these bioactive substances frequently since their half-life in a living body is generally short. Then, physical burden of patients due to administration by injection cannot be ignored. For example, growth hormone, a representative hormone which is originally produced and secreted in the anterior portion of the pituitary gland, is a bioactive peptide having widely diverse physiological activities such as, in addition to promotion of growth in the body, metabolism of saccharides and lipids, anabolism of proteins, cell proliferation and differentiation, and the like. At present, growth hormone is produced on a large scale by Escherichia coli using genetic recombination technology, and put to medicinal use clinically and worldwide. However, it is required to administer growth hormone frequently in order to maintain an effective blood level because of its short biological half-life. Especially, in the case of pituitary dwarfism, a daily subcutaneous administration to infants or young patients over a long period of time ranging from a few months to 10 years or more is actually taken place.
In order to deal with problems inherent in such bioactive substances, various drug delivery systems have been studied. For example, a sustained-release agent that provides sustained-release of a bioactive peptide over a long period of time has been studied. JP 8-217691 A (WO96/07399) discloses a method for producing a sustained-release preparation comprising a water-insoluble or poorly water soluble polyvalent metal salt of a water-soluble peptidic bioactive substance, which is formed by an aqueous solution of zinc chloride, etc., and a biodegradable polymer.
Further, for a sustained-release preparation using a biodegradable polymer, it is desired to maintain the activity of a bioactive substance with suppressing the initial release of a bioactive substance, in particular, release of the excess amount within one day, and to control the release of the bioactive substance arbitrarily over a long period of time. Regarding this problem, JP 11-322631 A discloses a method for producing a sustained-release preparation comprising adding a water-miscible organic solvent and/or a volatile salt to an aqueous solution of a bioactive peptide, followed by lyophilizing to obtain a bioactive peptide powder, dispersing the powder in a solution of a biodegradable polymer in an organic solvent, and removing the organic solvent. Furthermore, JP 9-132524 A discloses a method for producing sustained-release microcapsules comprising a bioactive substance and a biodegradable polymer which comprises, after forming microcapsules, heat-drying the microcapsules at a temperature of not less than the glass transition temperature of the biodegradable polymer for about 24 to 120 hours. These are methods for producing a sustained-release preparation containing very little residual organic solvent and having very superior clinical properties as medicaments.